Candida albicans is an opportunistic fungal pathogen that is able to survive as a commensal organism in several anatomically distinct sites. In compromised hosts, the manifestations of invasive infection caused by C. albicans vary based upon the particular anatomical origin of the causative strain. Phagocytes are the central effectors in host defense against hematogenously disseminated candidiasis. Using a new function-based approach, we have successfully identified a Candida albicans putative gene, HYR1, which encodes resistance to neutrophil-killing activity in vitro. In addition, we found that Bcr1p, a transcription factor positively regulating HYR1 expression, is also required for full resistance to neutrophil-killing. Based on these data, we hypothesize that Bcr1p, through the activation of its downstream effector, Hyr1p, contributes to survivability of C. albicans during hematogenous dissemination, increasing severity of infection. Our objective is to determine the impact of BCR1 during hematogenously disseminated candidiasis in mice, and to determine the relationship between BCR1 and HYR1 in regulating these processes. In this application, we will 1) determine the impact of BCR1 disruption on tissue fungal burden, inflammatory response and survivability during hematogenously disseminated murine candidiasis;and 2) determine if HYR1 autonomous expression complements the bcr1 null mutation in vitro and in vivo. While neutrophil-resistance mechanisms are well described for bacteria, the proposed studies will elucidate the first genetic relationship between an upstream regulator and a downstream effector for fungal resistance to neutrophil killing in vitro. Furthermore, the results of the proposed aims will define the in vivo effects of genes which control candidal resistance to phagocytic-killing in vitro. These studies will enable submission of a follow up R01 to identify additional members of the signal transduction pathway and to elucidate the mechanisms by which these genes mediate resistance to neutrophil killing in vitro and in vivo. As well, these putative virulence gene products will become potential targets for development of novel prophylactic and therapeutic strategies. PUBLIC HEALTH RELEVANCE: Candida is a cause of lethal infections in hospitalized patients. It is critical to understand how Candida causes such infections in order to create new ways to prevent and treat these infections. We have identified two genes that help the fungus to resist neutrophil killing in test tube. We will determine how these genes help the fungus to cause disease in mice, which will enable development of treatment strategies targeting these genes.